The obesity epidemic threatens a massive surge in metabolic disorders and other diseases including cancer. It is now known that inflammation can reinforce obesity and associated metabolic syndrome. This leads to chronic inflammation, which with other factors contribute to cancer risk. Reversing obesity or metabolic syndrome brings cancer risk toward normal levels. Natural Killer T cells (NKT) are conserved innate-like cells that can positively or negatively influence immune cells and therefore responses and outcomes in various models. We have reversed functional NKT defects in a cancer model and in vitro with human NKT. NKT are protective, but also reversibly depleted in obesity. The proposed studies will determine the mechanism for a novel role of NKT in metabolism and determine their therapeutic potential for treatment of metabolic syndrome, with implications for increased risk of cancer in obesity. Hypothesis: In obesity, we hypothesize that protective anti-tumor NKT cells are depleted throughout the body, contributing to loss of control of macrophages and consequent metabolic disease syndrome and increased cancer. This hypothesis leads to the following testable and not mutually exclusive predictions: a) Endoplasmic reticulum stress caused by obesity, leads to a loss of CD1d on the plasma membrane and therefore a decline in iNKT cells, and / or b) cancers that escape physiological control have suppressed iNKT, and this is more aggressive in obesity. Finally, there is the therapeutic question of how to reverse such defects in obesity, which we will also address. Aim 1: Determine whether cancer risk and aggressiveness are associated with iNKT loss in obesity. Aim 2: Determine whether reversing NKT cell defects can be protective in obesity-associated cancer. To perform these studies, we will exploit 2 models of cancer in which we have identified iNKT defects and combine these with obesity through high fat diets to test for increased aggressiveness. We will then determine optimal ways to reverse these defects and measure improvements in obesity, metabolic syndrome, and cancer. We are immuno-monitoring a trial of iNKT reconstitution in melanoma, so have experience in translating our findings to the clinic. PUBLIC HEALTH RELEVANCE: Obesity increases metabolic disorders and inflammatory diseases including cancer and inflammation can reinforce obesity, cancer, and associated metabolic syndrome. Natural Killer T cells ('NKT') recognize lipids bound to the CD1 molecule and we found that CD1 and NKT are enriched in liver and fat, depleted in cancer and obesity, but restored following weight loss and by NKT-targeted approaches. We will determine whether NKT dysfunction is exacerbated in obese cancer and their therapeutic potential.